Abstract 5169: Aurora-A kinase promotes anti-tumor immunity in high lymphocyte-infiltrated colorectal cancer
Authors: Shiang-Jie Yang, Ming-Derg Lai, Liang-Yi Hung
Journal: Cancer Research (2023)

Abstract Introduction: The tumor microenvironment (TME) is composed of different cell types and is involved in tumor progression. Several immunosuppressive signaling pathways can promote tumor growth by inhibiting anti-tumor immunity in TEM. Therefore, targeting the immunosuppressive signaling pathways is a potential cancer treatment. Recent studies reported that inhibition of oncoproteins could lead to reduced anti-tumor immunity in several cancers; therefore, it’s critical to identify the potential oncoproteins which can lead to enhanced anti-tumor immunity. Aurora-A is a serine/threonine kinase that plays an important role in the centrosome, cell mitosis, and chromosome stability. Previous studies indicated that cancer patients with poor prognoses are associated with a high Aurora-A level in tumor cells. Inhibition of Aurora-A is considered as a promising strategy for cancer treatment. However, Aurora-A inhibitors have not had a breakthrough in phase II or phase III clinical trials. The role of Aurora-A in tumor immunity is still unclear. Here, we investigated the role of Aurora-A in tumor immunity. Materials and Methods: shRNA was used to knock down Aurora-A, and Alisertib was added to inhibit Aurora-A. RT-qPCR and western blot were performed to determine the IL-16 expression. The secretion of cytokines was measured by cytokine array and ELISA. BALB/c and NOD/SCID mice were subcutaneously injected with CT26 and then administered daily with Alisertib or treated with anti-IL-16 antibody. The tumor-infiltrating immune populations were analyzed by flow cytometry. IHC and H/E stain were performed to analyze Aurora-A expression and lymphocyte infiltration in human CRC specimens. Results: CRC patients with lower lymphocyte infiltration and higher Aurora-A are associated with poor prognosis and vice versa. Knockdown of Aurora-A in CT26 promotes tumor growth in immunocompetent mice by inhibiting the infiltration and cytotoxic activity of CD8+ T cells. Aurora-A negatively regulates IL-16 expression in a kinase-dependent manner in CRC cells. Blockade of IL-16 by anti-IL-16 antibody can reverse the tumor growth and CD8+ T cell cytotoxic activity in Aurora-A knocked-down CT26 tumors. Alisertib can inhibit CT26 tumor growth and promote IL-16 secretion in TME in mice. A combination of Alisertib and IL-16 antibody can promote the therapeutic effect of Alisertib in CT26 tumors. Conclusion: Tumor-intrinsic Aurora-A plays a diverse role in tumor progression depending on the status of lymphocyte infiltration in TME. Aurora-A can promote anti-tumor immunity via negatively regulating IL-16 in a kinase activity-dependent manner in hot CRC tumors. In tumors with high lymphocyte infiltration, Aurora-A inhibition can suppress cancer cell growth and reduce anti-tumor immunity; the combination of Aurora-A inhibitors and IL-16 antibodies may provide a novel and effective strategy for cancer therapy in hot tumors. Citation Format: Shiang-Jie Yang, Ming-Derg Lai, Liang-Yi Hung. Aurora-A kinase promotes anti-tumor immunity in high lymphocyte-infiltrated colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5169.